DOCSLIB.ORG

ORIGINAL ARTICLE Sequence-Dependent Synergy Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ORIGINAL ARTICLE Sequence-Dependent Synergy Of Leukemia (2007) 21, 524–528 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu ORIGINAL ARTICLE Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma O Weigert1,2,3, A Pastore1,2,3, M Rieken2, N Lang1, W Hiddemann1 and M Dreyling1,2 1Department of Internal Medicine III, University of Munich, University Hospital Grosshadern, Munich, Germany and 2GSF-National Research Center for Environment and Health, Haematologicum, Munich, Germany Single-agent bortezomib, a potent, selective and reversible consisted of CHOP (cyclophosphamide, vincristine, doxorubi- inhibitor of the 26S proteasome, has demonstrated clinical cin and prednisone),12 R-FCM (rituximab, fludarabine, cyclo- efficacy in relapsed and refractory mantle cell lymphoma (MCL). 13 Objective response is achieved in up to 45% of the patients; phosphamide, and mitoxantrone) and gemcitabine/oxaliplatin however, complete remission rates are low and duration of with all relapses occurring within 1 year. No response was seen 90 response proved to be short. These limitations may be after radioimmunotherapy with rituximab/ Y-ibritumomab– overcome by combining proteasome inhibition with conven- tiuxetan 5 months earlier. Salvage therapy was started with tional chemotherapy. Here we present two case reports and in single-agent bortezomib 1.3 mg/m2 given intravenously twice vitro data suggesting synergistic efficacy of bortezomib weekly for 2 consecutive weeks, followed by a 1-week rest combined with cytarabine in MCL. Interestingly, efficacy in vitro correlated with sequence of treatment, indicating that period. Because of progressive lymphadenopathy at week 5, pretreatment with cytarabine, followed by proteasome inhibi- treatment was changed to a combination regimen consisting 2 tion, may be the preferred approach. of bortezomib (1.5 mg/m , days 1 and 4) and cytarabine Leukemia (2007) 21, 524–528. doi:10.1038/sj.leu.2404511; (1000 mg/m2 as a 3-h infusion on days 2 and 3) applied in published online 1 February 2007 3-week intervals. After two cycles, the leg edema and Keywords: non-Hodgkin’s lymphoma; mantle cell lymphoma; lymphadenopathy improved dramatically, and a very good bortezomib; cytarabine; combination treatment partial response was confirmed by computer tomography (CT) scanning (Figure 1a and b). Because of NCI/CTC grade 4 neutropenia after cycle 2, the dose of cytarabine was reduced to 75% and granulocyte-colony-stimulating factor (G-CSF) support was initiated. Importantly, there was no infectious complication Introduction and only cycle 4 had to be delayed for 1 week. Because of NCI/ CTC grade 3 sensory peripheral neuropathy after cycle 2, The ubiquitin–proteasome pathway is essential for maintaining bortezomib was omitted during the subsequent two cycles with intracellular protein homeostasis and represents a valid target for polyneuropathy gradually improving; the hematologic toxicity the treatment of malignant disease.1 Various oncogenes and did not differ significantly after bortezomib was held. Except for regulatory proteins for cell cycle progression and apoptosis are alopecia, there was no additional significant non-hematological processed by this pathway.2 Bortezomib is a potent, selective toxicity. Meanwhile, 11 months (343 days) after initiation of and reversible inhibitor of the proteasome with demonstrated combination therapy, the patient suffered from systemic progres- efficacy in relapsed multiple myeloma.3,4 Single-agent bortezo- sion and was started on a bendamustin-containing regimen. mib demonstrated clinical activity in several other hematologic malignancies5 with especially encouraging results in relapsed or 6–8 refractory mantle cell lymphoma (MCL). Objective response Case report 2 is achieved in 29–45% of MCL patients; however, complete A 63-year-old woman with relapsed stage IV MCL presented remission rates are low and median duration of response short. with progressive abdominal lymphadenopathy and reappear- These limitations may be overcome by combining bortezomib ance of extensive watery diarrhea, attributable to exacerbation 9,10 with conventional chemotherapy. Feasibility has been of colonic infiltration, confirmed by colonoscopy after 10 cycles 11 demonstrated for liposomal doxorubicin. We present two of single-agent bortezomib therapy (1.3 mg/m2 intravenous, case reports and in vitro data suggesting a sequence-dependent days 1, 4, 8, 11, every 3 weeks). Four years earlier, the disease synergy of bortezomib and cytarabine in MCL. was diagnosed with colonic polyposis and infiltration of the stomach, the nasopharynx, the right lacrimal gland and bone marrow involvement. Previous treatment consisted of CHOP Case report 1 followed by interferon maintenance,12 R-FCM13 and radio- A 67-year-old man with relapsed stage IV MCL presented with immunotherapy with rituximab/90Y-ibritumomab–tiuxetan. The progressive bilateral leg edema caused by extensive inguinal, best response consisted of partial remission, and duration of iliac and paraaortic lymphadenopathy. Previous treatment response declined from initially observed 21 months with every consecutive line of treatment. Single-agent bortezomib treat- Correspondence: Professor M Dreyling, Department of Medicine III, ment resulted in a decreased frequency of diarrhea by cycle 4, University Hospital Grosshadern, Marchioninistrasse 15, D-81377 which however, failed by cycle 10. Treatment was changed to Munich, Germany. the combination regimen, consisting of bortezomib (1.5 mg/m2, E-mail: [email protected] 2 3These authors contributed equally to this work days 1 and 4) and cytarabine (1000 mg/m as a 3-h infusion on Received 21 April 2006; revised 3 October 2006; accepted 11 days 2 and 3), applied in 4-week intervals with rituximab added October 2006; published online 1 February 2007 on day 0 (375 mg/m2). Because of NCI/CTC grade 1 sensory Synergy of bortezomib and cytarabine in MCL O Weigert et al 525 Proliferation assay Cells were seeded at a density of 5 Â 105/ml in the absence or presence of bortezomib (25 nM). Cells were counted in a hematocytometer, and viability of cells was assessed by Trypan blue exclusion test (Gibco, Invitrogen, Karlsruhe, Germany) at 0, 24, 48 and 96 h of treatment. Apoptosis assay Cells were washed and stained with Annexin V-PE/7–AAD in accordance with the manufacturer’s protocol (BD Biosciences, Heidelberg, Germany) and subjected to flow cytometry (BD FACS Calibur, BD Biosciences, Palo Alto, CA, USA). Apoptosis rate was calculated as follows: 0fraction viable treated cells0 1 À Â100%: 0fraction viable untreated cells0 Spontaneous apoptosis rate was up to 10% for established MCL cell lines and up to 25% for MCL cells derived from patient samples. Figure 1 Clinical efficacy of bortezomib and cytarabine in MCL. CT Cell viability assay and determination of Chou and scans before (a and c) and after two cycles (b and d) of combination Talalay’s combination index treatment with cytarabine and bortezomib demonstrating significant Cell viability correlates with the activity to metabolize the decrease of lymphadenopathy (arrows). tetrazolium salt WST-1 to a water-soluble formazan dye, which is measured spectrophotometrically. Cells were seeded at a density of 1 Â 106/ml in a 96-well microplate in triplicate (100 000 cells/well) and the assay was performed according to peripheral neuropathy, the dose of bortezomib was reduced to the manufacturer’s protocol (Roche Applied Science, Man- 1.0 mg/m2 during cycles 2–4. The diarrhea improved rapidly nheim, Germany). The half maximal inhibitory concentration and disappeared subsequently. After two and four cycles, a (IC ) was used for calculation of Chou and Talalay’s combina- complete disappearance of pathological lymphadenopathy was 50 tion index (CI ) applying CalcuSyn Software (Biosoft, Cam- confirmed by CT scanning (Figure 1c and d). Endoscopically, the 50 bridge, UK) as described previously.14 This index allows polypoid lesions decreased substantially however, residual MCL identification of antagonistic (CI 41.3), additive (CI ¼ infiltration was seen on biopsy specimen. A partial remission 50 50 170.3) or synergistic (CI 0.7) efficacy of combination was diagnosed and no further treatment was applied to the 50 o treatment by considering cell viability curves determined after asymptomatic patient. NCI/CTC grade 3/4 toxicity consisted 12 and 24 h of treatment with cytarabine alone, bortezomib mainly of myelotoxicity, with neutropenia requiring G-CSF alone or in combination (synchronous and sequential incuba- support and one episode of neutropenic fever requiring empiric tion) of both, respectively. antibiotic treatment. There was no treatment delay and no dose reduction of cytarabine. Meanwhile, the patient has remained in documented ongoing remission for more than 7 months (233 Statistical analysis days) after initiation of combination treatment with no disease- A two-sided Student’s t-test was applied when indicated. related symptoms. Results Materials and methods At clinically achievable concentrations, bortezomib (25 nM) Cell culture and reagents inhibited cell growth in all cell lines in a time-dependent Established MCL cell lines consisted of Granta519, HBL-2 and manner, with MCL demonstrated to be more sensitive than the Jeko-1; the T-ALL cell line Jurkat was used as hematologic hematological control cell line Jurkat (Figure 2a, Po0.01 for control cell line; all established cell lines were obtained from MCL vs non-MCL cell lines at 48 and
Load more

Recommended publications
  • A Phase II Study of the Novel Proteasome Inhibitor Bortezomib In
    Memorial Sloan-Kettering Cance r Center IRB Protocol IRB#: 05-103 A(14) A Phase II Study of the Novel Proteas ome Inhibitor Bortezomib in Combination with Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory I Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL Principal Investigator: John Gerecitano, M.D., Ph.D. Co-Principal Carol Portlock, M.D. Investigator(s): IFormerly: A Phase I/II Study of the Nove l Proteasome Inhibitor Bortezomib in Combinati on with Rituximab, Cyclophosphamide and Prednisone in Patients with Relapsed/Refractory Indolent B-cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL) Amended: 07/25/12 Memorial Sloan-Kettering Cance r Center IRB Protocol IRB#: 05-103 A(14) Investigator(s): Paul Hamlin, M.D. Commack, NY Steven B. Horwitz, M.D. Philip Schulman, M.D. Alison Moskowitz, M.D. Stuart Lichtman, M.D Craig H. Moskowitz, M.D. Stefan Berger, M.D. Ariela Noy, M.D. Julie Fasano, M.D. M. Lia Palomba, M.D., Ph.D. John Fiore, M.D. Jonathan Schatz, M.D. Steven Sugarman, M.D David Straus, M.D. Frank Y. Tsai, M.D. Andrew D. Zelenetz, M.D., Ph.D. Matthew Matasar, M.D Rockville Center, NY Mark L. Heaney, M.D., Ph.D. Pamela Drullinksy, M.D Nicole Lamanna, M.D. Arlyn Apollo, M.D. Zoe Goldberg, M.D. Radiology Kenneth Ng, M.D. Otilia Dumitrescu, M.D. Tiffany Troso-Sandoval, M.D. Andrei Holodny, M.D. Sleepy Hollow, NY Nuclear Medicine Philip Caron, M.D. Heiko Schoder, M.D. Michelle Boyar, M.D.
    [Show full text]
  • VELCADE® (Bortezomib) for Injection
    1 VELCADE® (bortezomib) for Injection 2 PRESCRIBING INFORMATION 3 DESCRIPTION 4 VELCADE® (bortezomib) for Injection is an antineoplastic agent available for intravenous 5 injection (IV) use only. Each single dose vial contains 3.5 mg of bortezomib as a sterile 6 lyophilized powder. Inactive ingredient: 35 mg mannitol, USP. 7 Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic 8 ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its 9 hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic 10 anhydride form as a trimeric boroxine. 11 The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1- 12 oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. 13 Bortezomib has the following chemical structure: O OH H N N B N OH H O N 14 15 The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of 16 bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 17 6.5. 18 CLINICAL PHARMACOLOGY 19 Mechanism of Action 20 Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in 21 mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated 22 proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular 23 concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of 24 the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling 25 cascades within the cell.
    [Show full text]
  • Combining Milatuzumab with Bortezomib, Doxorubicin, Or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R
    CancerTherapy: Preclinical Combining Milatuzumab with Bortezomib, Doxorubicin, or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines Rhona Stein,1Mitchell R. Smith,2 Susan Chen,1Maria Zalath,1and David M. Goldenberg1 Abstract Purpose: The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2. Experimental Design: Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM. Results: Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded sig- nificant antiproliferative effects in CD74+ cells.The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC50 of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-nB pathwayinCAGMMcells. In CAG-or KMS11-SCIDxenograftmodels ofdisseminated MM, milatuzumab more than doubled median survival time, compared withup to a 33% increase in median survival withbortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumabandbortezomibincreasedsurvivalsignificantlycomparedwitheither treatmentalone. Conclusions:The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are en- hanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically.
    [Show full text]
  • Antitumor Effects of Bortezomib (PS-341) on Primary Effusion Lymphomas
    Leukemia (2004) 18, 1699–1704 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00 www.nature.com/leu Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas JAn1, Y Sun1, M Fisher1 and MB Rettig1,2 1VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; and 2Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA Primary effusion lymphomas (PELs) are a rare type of non- treatment of refractory multiple myeloma, where it has an Hodgkin’s lymphoma that are resistant to cytotoxic chemother- acceptable toxicity profile.4–6 By inhibiting the proteasome, apy. PELs manifest constitutive activation of nuclear factor kappa B (NF-jB), and inhibition of NF-jB induces apoptosis of which degrades proteins that are marked by ubiquitination, PELs and sensitizes to tumor necrosis factor-related apoptosis- bortezomib modulates the cellular concentrations of hundreds inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a of proteins that are involved in a wide variety of functions, peptidyl boronic acid inhibitor of the proteasome, is a potent including cell cycle progression, signal transduction, and agent against a wide range of hematologic malignancies and apoptosis.7,8 For example, the proteasome regulates the activity has been shown to inhibit NF-jB. Thus, we examined the of the NF-kB pathway, in that the degradation of I kappa B (IkB), cytotoxic effects of bortezomib alone and in combination with the NF-kB inhibitory protein, is dependent upon the ubiquitin– various drugs. Bortezomib potently inhibited NF-jB in PEL cells 9 in a dose-dependent manner.
    [Show full text]
  • Bortezomib Plus Docetaxel in Advanced Non-Small Cell Lung Cancer and Other Solid Tumors: a Phase I California Cancer Consortium Trial
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector ORIGINAL ARTICLE Bortezomib Plus Docetaxel in Advanced Non-small Cell Lung Cancer and Other Solid Tumors: A Phase I California Cancer Consortium Trial Primo N. Lara, Jr., MD,*† Mariana Koczywas, MD,‡ David I. Quinn, MD, PhD,§ Heinz Josef Lenz, MD,§ Angela M. Davies, MD,* Derick H.M. Lau, MD, PhD,*† Paul H. Gumerlock, PhD,* Jeff Longmate, PhD,‡ James H. Doroshow, MD,‡ David Schenkein, MD,͉͉ Oscar Kashala, MD,͉͉ and David R. Gandara, MD*† n recent years, the inhibition of the 26S proteasome has Background: This phase I study was performed to determine the emerged as a rational anti-neoplastic strategy. The 26S dose-limiting toxicity and maximum tolerated dose (MTD) of do- I proteasome is a very large proteolytic complex involved in a cetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. significant catabolic pathway, the ubiquitin–proteasome path- way, for many intracellular regulatory proteins, including I␬B Methods: Patients were enrolled in cohorts of three over six dose ␬ ␬ ␬ levels. Each treatment cycle was 3 weeks long and consisted of one kinase/nuclear factor- B(I B/NF- B), p53, and the cyclin- docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, dependent kinase inhibitors p21 and p27, which contribute to 8, and 11). Dose escalation and MTD determination were based on the regulation of the cell cycle, apoptosis, and angiogene- 1–3 the occurrence of dose-limiting toxicities in cycle 1 only.
    [Show full text]
  • Thesis Biochemistry By
    Ain shams Universirty Faculty Of Science Evaluation of anticancer effects of a novel proteasome inhibitor (Velcade), interferon (alpha-interferon) and antimyeloma antibodies on the growth of myeloma cells. Thesis Submitted for the Requirement of the Ph.D degree in Biochemistry By Hanan Mohammed Mohammed El shershaby. (M.Sc in Biochemistry) Under Supervision of Prof.Dr / Ibrahim Hassan Borai Prof.Dr/ Mohamed Taha Hussein El- Kolaly Prof. of Biochemistry Professor of Radiopharmaceutics Faculty Of Science Atomic Energy Authority Ain shams Universirty Prof.Dr/Naser Mohammed El-lahloby Prof. Dr/ Kamel Abd El.hameed Moustafa Prof. of Medical Oncology Professor of Biochemistry Cancer Institute Center Atomic Energy Authority Cairo University Dr / Ahmed Abd El.aziz sayed Assistant professor of Biochemistry Faculty Of Science Ain shams Universirty (2013) CONTENTS Introduction and Aim of the work 1 Review Of Literature 4 ◙ Multiple Myeloma 4 ◙ Cell cycle 16 ◙ Apoptosis 19 ◙ Caspases 23 ◙ Chemotherapy 25 ◙ Proteasomes 36 Bortezomib (Velcade) 38 ◙ Interferons 43 ◙ Immunity and Immune system 46 Antibodies 49 Production of Antibodies 51 ◙ Immunotherapy 57 ◙ Radioimmunotherapy ( RIT ) 61 ◙ Gene therapy 62 Materials and Methods 64 Results 92 Discussion 133 Summary 144 References 148 Arabic Summary LIST OF FIGURES Figure (1): Overview of the cell cycle. 16 Figure (2): Apoptosis – the programmed death of a cell. 20 Figure (3): The intrinsic and extrinsic pathways leading to apoptosis. 22 Figure (4): Structure of the 26S proteasome. 37 Figure (5): Chemical Structure of Bortezomib 38 Figure (6): Mechanism of action of Bortezomib 40 Figure (7): The different ways that Bortezomib can affect multiple myeloma 41 Figure (8): Antitumor actions of interferons.
    [Show full text]
  • Velcade, INN-Bortezomib
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Velcade. This scientific discussion has been updated until 1 May 2004. For information on changes after this date please refer to module 8. 1. Introduction Multiple myeloma Multiple myeloma is a B-cell malignancy of the plasma cell and represents the second most common hematological malignancy, with non-Hodgkin’s lymphoma being the most common. The incidence and prevalence of multiple myeloma are similar in the US and Europe. In 2000, there were approximately 19,000 cases diagnosed in the European Economic Area (Globocan, 2000), with a 5- year prevalence of approximately 47,000 cases. The course of multiple myeloma is characterized by an asymptomatic or subclinical phase before diagnosis (possibly for several years), a chronic phase lasting several years, and an aggressive terminal phase. Multiple myeloma leads to progressive morbidity and eventual mortality by lowering resistance to infection and causing significant skeletal destruction (with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, and, less commonly, neurological complications and hyperviscosity. From the time of diagnosis, the survival without treatment is between 6 to 12 months and extends to 3 years with chemotherapy. Approximately 25% of patients survive 5 years or longer, with fewer than 5% surviving longer than 10 years. Approved anticancer agents for the treatment of myeloma in the US include melphalan (1992), carmustine (BCNU, 1977) and cyclophosphamide (1959) and in addition, in Europe, epirubicin is also approved for treatment of this disease. At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that varies on the basis of both disease- and host-related factors (e.g., age, renal function, stage, alpha2- microglobulin, chromosomal abnormalities).
    [Show full text]
  • Generated by Bortezomib Immune Mechanism of the Antitumor Effects
    The Journal of Immunology Immune Mechanism of the Antitumor Effects Generated by Bortezomib Chih-Long Chang,*,†,‡ Yun-Ting Hsu,† Chao-Chih Wu,† Yuh-Cheng Yang,* Connie Wang,x T.-C. Wu,x,{,‖,# and Chien-Fu Hungx,{ Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation.
    [Show full text]
  • Prescribing Information | VELCADE® (Bortezomib)
    HIGHLIGHTS OF PRESCRIBING INFORMATION Hypotension: Use caution when treating patients taking These highlights do not include all the information needed to antihypertensives, with a history of syncope, or with dehydration. use VELCADE safely and effectively. See full prescribing (5.2) information for VELCADE. Cardiac Toxicity: Worsening of and development of cardiac VELCADE® (bortezomib) for injection, for subcutaneous or failure has occurred. Closely monitor patients with existing heart intravenous use disease or risk factors for heart disease. (5.3) Initial U.S. Approval: 2003 Pulmonary Toxicity: Acute respiratory syndromes have ------------------------RECENT MAJOR CHANGES-------------------------- occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. (5.4) Warnings and Precautions, Posterior Reversible Encephalopathy Syndrome: Consider MRI Thrombotic Microangiopathy (5.10) 04/2019 imaging for onset of visual or neurological symptoms; ------------------------INDICATIONS AND USAGE-------------------------- discontinue VELCADE if suspected. (5.5) VELCADE is a proteasome inhibitor indicated for: Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and treatment of adult patients with multiple myeloma (1.1) vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (5.6) treatment of adult patients with mantle cell lymphoma (1.2) Thrombocytopenia and Neutropenia: Monitor complete blood ----------------------DOSAGE AND ADMINISTRATION---------------------
    [Show full text]
  • Recent Advances in the Management of Hormone Refractory Prostate Cancer
    Korean J Uro-Oncol 2004;2(3):147-153 Recent Advances in the Management of Hormone Refractory Prostate Cancer Mari Nakabayashi, William K. Oh Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA A typical treatment strategy after AAWD is to use secondary INTRODUCTION hormonal manipulations, although studies have not yet demonstrated a survival benefit with this class of treatment. Prostate cancer is the most common cancer in men in the Options in this category include (1) the secondary use of anti- United States and accounted for 29,900 deaths in 2003.1 androgens (e.g., high-dose bicalutamide, nilutamide), (2) thera- Although most men with advanced prostate cancer respond pies targeted against adrenal steroid synthesis (e.g., ketocona- initially to androgen deprivation therapies (ADT) by either zole, corticosteroids), and (3) estrogenic therapies (e.g. diethy- bilateral orchiectomy or leuteinizing hormone releasing hor- lstilbestrol). Symptomatic improvement and PSA responses mone (LHRH) analogues, patients eventually progress to an (defined as PSA decline ＞50% after treatment) have been androgen-independent state in which the initial ADT no longer reported in approximately 20% to 80% of patients with is adequate to control disease.2 Progression of the disease hormone-refractory prostate cancer (HRPC) with a typical manifests as an increase in serum prostate-specific antigen duration of response of 2 to 6 months. Toxicity is generally (PSA) or may be accompanied by radiographic evidence of mild for these oral therapies, although serious side effects, tumor growth. Here we report a brief summary of recent including adrenal insufficiency, liver toxicity, and thrombosis, advances in the management of hormone refractory prostate may occur (Table 1).
    [Show full text]
  • Cancer Nanobiotechnolgy
    Acta Pharmacologica Sinica (2017) 38: 735–737 © 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps Editorial Cancer nanobiotechnolgy Yong-zhuo HUANG*, Ya-ping LI Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Acta Pharmacologica Sinica (2017) 38: 735–737; doi: 10.1038/aps.2017.48 Advanced drug delivery techniques have been applied in uptake. Zhang and Wu et al[4] developed a dual-targeting cancer therapy to improve treatment outcomes and reduce hybrid nanoparticles for codelivery of doxorubicin (DOX) and adverse effects, and already achieved promising progress. In mitomycin C (MMC). The polymer-lipid hybrid nanoparticles particular, nanobiotechnology plays an increased important were modified by the vα β3 integrin-binding RGD peptide, thus role in combating cancer. Nano drug delivery systems can achieving a from-tissue-to-cell dual targeting, because both the improve the pharmacokinetics profiles and tumor biodistribu- angiogenic tumor vascular endothelium and invasive breast [5] tion of the antitumor drugs and their intracellular delivery; in cancer cells overexpress αvβ3 integrin. Sun and Huang et al addition, the drug instability and water insolubility problems designed a from-cell-to-mitochondria dual-targeting delivery can be solved by encapsulation into the nano systems. system by using the G13-C12 peptide targeting galectin-3 that Ideal delivery of antitumor drugs should maximize drug is highly expressed on the PC-3 human prostate cancer cells accumulation at tumors while minimize the unwanted drug and then redistributes to the mitochondria. Kang and Huang exposure to normal tissues, thus executing cytotoxicity specifi- et al[6] used the mannose-mediated tumor targeting liposomes cally in cancer cells and sparing normal cells[1].
    [Show full text]
  • WO 2016/179306 Al 10 November 2016 (10.11.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/179306 Al 10 November 2016 (10.11.2016) P O P C T (51) International Patent Classification: 358508 (SG). RASHID, Masturah Mohd Abdul; BLK A61K 31/706 (2006.01) A61K 31/573 (2006.01) 456, Hougang Ave. 10, #04-445, Singapore 530456 (SG). A61K 31/407 (2006.01) A61K 31/404 (2006.01) (74) Agents: LIU, Cliff Z. et al; Foley & Lardner LLP, 3000 K A61K 31/69 (2006.01) A61P 35/00 (2006.01) Street N.W., Suite 600, Washington, District of Columbia A61K 31/13 (2006.01) 20007-5 109 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 16/0308 19 kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 4 May 2016 (04.05.2016) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/157,348 5 May 2015 (05.05.2015) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicants: THE REGENTS OF THE UNIVERSITY TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]